Stable reagents for the generation of N-centered radicals: Hydroamination of norbornene

Article abstract of DOI:10.1002/anie.200463032

(Chemical Equation Presented) Radical transfer hydroaminations have been achieved with 3-aminated 1,4-cyclohexadienes rather than transition-metal reagents (see scheme; DTBP = di-tert-butylperoxide). These functionalized cyclohexadienes are efficient N-radical precursors. Moreover, they are stable and readily prepared, and radical generation occurs under neutral conditions.

Full text of DOI:10.1002/anie.200463032

Communications
Radical Chemistry
DOI: 10.1002/anie.200463032
Stable Reagents for the Generation of
N-Centered Radicals: Hydroamination of
Norbornene**
Jens Kemper and Armido Studer*
The transition-metal-mediated hydroamination of olefins has
been investigated intensively during the last few years.
Despite these efforts the methods developed so far are still
limited to activated systems.[1] Radical chemistry may be an
alternative. However, radical additions of amines or amine
derivatives to olefins by H-transfer processes are not known
to date. Whereas the addition of N radicals to alkenes is well
established,[2,3] the H transfer from N to C radicals is not an
efficient process [Eq. (1)]. In fact, the reverse reaction, H
transfer from C to N, has been successfully used. The well-
known Hofmann–Löffler–Freytag reaction is an example.[4]
N radicals are generally generated via N–halogen, N-
PTOC (PTOC = N-hydroxypyridine-2(1H)thione) and N-
phenylthio derivatives either photochemically or by using
an added reducing reagent.[2] However, most of these
precursors are unstable and must be prepared in situ.
Herein we present new stable N-radical precursors. More-
over, we show that these reagents can be applied for the
intermolecular hydroamination of norbornene derivatives
and electron-rich olefins.
Walton et al. nicely demonstrated that substituted 1,4-
cyclohexadienes can be used as precursors for C radicals.[5] We
have further extended this concept to the generation of Si
radicals.[6] Based on these results we assumed that 3-N-
substituted 1,4-cyclohexadienes can be used as new stable N-
radical precursors for the transition-metal-free transfer
hydroamination of alkenes (Scheme 1). Addition of an N
radical to an alkene will afford the corresponding C radical,
[*] Dr. J. Kemper, Prof. Dr. A. Studer
Westfälische-Wilhelms-Universität Münster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Münster (Germany)
Fax: (+49)251-833-6523
E-mail: studer@uni-muenster.de
[**] This research was supported by the Studienstiftung des deutschen
Volkes (stipend for J.K). We thank J. Guin and F. Schleth for
conducting some of the hydroamination experiments and K. Müller
for preparing the norbornene derivatives.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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11, however, toluene (around 16% yield) was identified as a
product of aromatization. Compounds 7 and 12 turned out to
be highly unstable: they underwent complete aromatization
yielding methyl 2,4-dimethylbenzoate and toluene, respec-
tively, in the stability test experiments. Hence, substituent at
the 1-position of the cyclohexadiene that would destabilize a
positive charge is important to suppress ionic decomposition.
The radical amination of norbornene using reagent 9
(!13) was studied next. Optimizations were conducted in
benzene in sealed tubes at 1408C using di-tert-butylperoxide
(DTBP) as an initiator (Table 1). We were very pleased to
Table 1: Reaction of norbornene with 9 to give 13 under different
conditions.
Scheme 1. Radical transfer hydroamination.
Run
9
Norbornene
[equiv]
DTBP
[equiv]
c [m]
Yield
[%][a]
[equiv]
which should be reduced with 1 to provide 2 and the desired
hydroamination product. Chain propagation should occur
through aromatization of 2 to deliver an N-radical and 3. The
intrinsically difficult H transfer from N to C is replaced by a
known H-transfer process. Since no additional reducing
reagent is necessary, 1 can be regarded as a hydroamination
reagent.
The syntheses of the reagents are depicted in Scheme 2.
Ester 4 was readily prepared from commercially available
materials by a Wittig reaction. Saponification and a Schmidt-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1
1
1
1
1
1
1
1
1
1
2
4
5.7
1
1
1
1
1.0
1.1
1.1
1.1
1.1
2.0
3.0
4.3
5.3
7.0
1.0
1.0
1.0
2.9
3.1
3.0
2.9
0.3
0.4
0.6
0.8
1.0
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.5
0.4
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.18
0.18
0.18
0.5
30
36
30
30
28
44
45
39
39
37
41
42
57
41
37
38
38
0.76
1.0
–
[a] Determined by GC analysis with methyl benzoate as an internal
standard.
observe that metal-free transfer hydroamination occurred.
Variation of the initiator concentration revealed that the best
results (36% yield) for the reaction with 1 equiv of 9 and
1.1 equiv of norbornene at a concentration of 0.25m were
obtained with 0.4 equiv of peroxide (runs 1–5). Higher yields
were obtained with 2 or 3 equivs of olefin (44 and 45%,
runs 6,7). However, a further increase of the norbornene
concentration did not lead to better results (runs 8–10). The
highest yield was obtained when 9 was used in a large excess:
with a 5.7-fold excess a 57% yield was obtained (run 13).
Running the aminations at higher concentrations provided
lower yields (runs 15,16). We found that the amination can be
performed under solvent-free conditions (run 17). As a result
of the optimization studies all subsequent experiments were
performed with a threefold excess of olefin at a concentration
of 0.25m with 0.4 equiv of initiator.
The yield was improved further upon switching from the
Moc derivative 9 to the Boc-protected reagent 8 (!14, 56%).
As expected from the stability tests, cyclohexadiene 7 is not
an efficient hydroamination reagent (!14, 18%). We also
believe that the aromatization step delivering the carbamoyl
radical is very slow for the cyclohexadienyl radical arising
from 7. Indeed, the methyl fragmentation product methyl 2-
tert-butoxycarbonylaminyl-4-methyl benzoate was isolated as
Scheme 2. a) NaOH, MeOH; b) Et3N, ClC(O)OEt; c) NaN3, H2O;
d) tBuOH or MeOH, toluene, reflux; e) methyl propiolate, dioxane,
1108C; f) 1. 3-nitromethylacrylate, benzene; 2. DBU. g) 1. 3-nitroacrylo-
nitrile, benzene; 2. DBU. Boc=tert-butoxycarbonyl, DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene, Moc=methoxycarbonyl.
type rearrangement followed by alcoholysis of the intermedi-
ate isocyanate provided dienes 5 and 6. Cyclohexadienes 8–10
were prepared by a Diels–Alder reaction using dienes 5 and 6.
The syntheses of cyclohexadienes 11 and 12 are described in
the Supporting Information.
We first tested the stability of the reagents. To this end,
dienes 7–12 were heated in C6D6 in sealed tubes at 1408C (oil
bath temperature) for 18 h. No decomposition was observed
for compounds 8–10 as judged by 1H NMR spectroscopy. For
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Communications
the major product in 44% yield. The position of the electron-
hydroamination product 21 in 48% yield.[8,9] Carbamoyl
radical addition onto vinyl pivalate delivers a nucleophilic a-
oxy radical, and a polar effect should favor H abstraction
from the electronegative thiol. The electrophilic thiyl radical
generated in this way will, in turn, abstract an H atom more
readily from the cyclohexadienyl site of 8, thus regenerating
the thiol catalyst and continuing the chain (polymerization is
suppressed).[8] Vinyl phthalimide was also successfully hydro-
aminated in the presence of 10% thiol catalyst (!22, 43%).
The highest yield was obtained for the hydroamidation of
dihydropyran (!23, 60%).[10]
withdrawing group is obviously important. However, the
methoxycarbonyl substituent can be replaced by a cyano
group without affecting the yield greatly. Thus, the reaction
with 10 afforded 14 in 45% yield. Substituents at the vinylic
positions of our reagents are not mandatory. Amination using
the unsubstituted diene 11 provided 14 in 47% yield. As
expected, hydroamination of norbornene with phthaloyl-
protected cyclohexadiene 12 did not work. The stability of 12
is a problem, as shown by the tests discussed above. More-
over, the addition of the sterically hindered N-phthaloyl
radical is probably slow. Phthalimide was isolated in 61%
yield. Our method delivers the amination products as Boc- or
Moc-protected derivatives. This is highly desirable since most
of the chemical manipulations on amine-functionalized
molecules require N protection.
Finally, the most efficient reagents identified (8,9) were
used to study other hydroaminations (Scheme 3). Products
15–19 were obtained in moderate-to-good yields as 1:1
mixtures of regioisomers. Hydroamination of benzannulated
norbornene with 8 provided 20 in 40% yield. Hydroamination
of vinyl pivalate under standard conditions afforded 21 along
with telomers comprising two, three, and four monomer units,
as identified by ESI-MS. Obviously, reduction of the a-oxy
radical generated after N-radical addition onto vinyl pivalate
cannot efficiently compete with telomerization. However, we
found that this problem can be circumvented upon using
polarity reversal catalysis.[7] Thus, hydroamination in the
presence of methyl thioglycolate (10%) delivered the desired
As expected, addition of the electrophilic carbamoyl
radicals derived from 8 or 9 onto electron-deficient olefins
such as acrylonitrile and butyl acrylate did not occur.
Pleasingly, we found that the highly challenging hydroamina-
tion of 1-octene could be accomplished (!24). Although the
yield is currently not satisfactory (17%), manipulation of the
electronic nature of the N-centered radical (varying the N-
protecting group) should allow increasing the efficiency of the
process. Workalong this line is currently under way.
In conclusion we have presented a new method for the
generation of N radicals under neutral conditions. In contrast
to well-established procedures using N–halogen derivatives as
N-radical precursors,[2] an additional stoichiometric reducing
reagent such as the toxic tributyltin hydride is not necessary
for N-radical generation. Moreover, the radical precursors are
readily prepared and are stable compounds. To the best of our
knowledge, this is the first report on a radical hydroamination
reagent. Moreover, transition-metal-free transfer hydroami-
nations are unknown.[11]
Received: December 22, 2004
Revised: May 5, 2005
Published online: July 6, 2005
Keywords: hydroaminations · radical chemistry ·
.
synthetic methods
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Breindl, M. Eichberger, C. G. Hartung, J. Seayad, O. R. Thiel, A.
Tillack, H. Trauthwein, Synlett 2002, 1579; For a review in
hydroaminations of alkynes, see: S. Doye, Synlett 2004, 1653.
[2] L. Stella, Angew. Chem. 1983, 95, 368; Angew. Chem. Int. Ed.
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[3] Recent examples on intermolecular addition of N-centered
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2003, 68, 3246; O. Kitagawa, S. Miyaji, Y. Yamada, H. Fujiwara,
T. Taguchi, J. Org. Chem. 2003, 68, 3184; O. Kitagawa, Y.
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Angew. Chem. Int. Ed. 2001, 40, 3865.
[4] P. Mackiewicz, R. Furstoss, Tetrahedron 1978, 34, 3241.
[5] G. Binmore, J. C. Walton, L. Cardellini, J. Chem. Soc. Chem.
Commun. 1995, 27; P. A. Baguley, G. Binmore, A. Mine, J. C.
Walton, Chem. Commun. 1996, 2199; P. A. Baguley, J. C. Walton,
J. Chem. Soc. Perkin Trans. 1 1998, 2073; L. V. Jackson, J. C.
Walton, Chem. Commun. 2000, 2327; L. V. Jackson, J. C. Walton,
J. Chem. Soc. Perkin Trans. 2 2001, 1758; A. F. Bella, L. V.
Jackson, J. C. Walton, J. Chem. Soc. Perkin Trans. 2 2002, 1839;
Scheme 3. Hydroamination of various olefins. Pht=Phthaloyl.
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A. F. Bella, A. M. Z. Slawin, J. C. Walton, J. Org. Chem. 2004, 69,
5926.
[6] A. Studer, S. Amrein, Angew. Chem. 2000, 112, 3196; Angew.
Chem. Int. Ed. 2000, 39, 3080; S. Amrein, A. Timmermann, A.
Studer, Org. Lett. 2001, 3, 2357; S. Amrein, A. Studer, Chem.
Commun. 2002, 1592; S. Amrein, A. Studer, Helv. Chim. Acta
2002, 85, 3559; A. Studer, S. Amrein, F. Schleth, T. Schulte, J. C.
Walton, J. Am. Chem. Soc. 2003, 125, 5726.
[7] B. P. Roberts, Chem. Soc. Rev. 1999, 28, 25.
[8] A. F. Bella, L. V. Jackson, J. C. Walton, Org. Biomol. Chem.
2004, 2, 421.
[9] In the presence of 30% thiol catalyst the yield decreased (28%)
and thiyl radical addition to vinyl pivalate was observed as a side
reaction.
[10] The regioisomeric hydroamination product, the cyclic N,O
acetal, was formed in 5% yield.
[11] For recent reports on transition-metal-free transfer hydrogena-
tion see: J. W. Yang, M. T. Hechavarria Fonseca, B. List, Angew.
Chem. 2004, 116, 6829; Angew. Chem. Int. Ed. 2004, 43, 6660;
J. W. Yang, M. T. Hechavarria Fonseca, B. List, Angew. Chem.
2005, 117, 110; Angew. Chem. Int. Ed. 2005, 44, 108; S. G.
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2005, 127, 32.
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